Selectively delivering particles into the distal portion of the left gastric artery

ABSTRACT

Methods and apparatuses for embolizing an artery in a living subject using a catheter are disclosed. The catheter has a lumen and also has a balloon located near the distal end of the catheter. The distal end of the catheter is introduced into the artery, and the balloon is inflated to form a seal that prevents blood in the artery from flowing past the balloon. A mixture that includes embolic particles and contrast agent is injected through the lumen into the portion of the artery that is distally beyond the balloon. The subject&#39;s own blood or another fluid that contains platelets is injected through the lumen into the portion of the artery that is distally beyond the balloon. Subsequently, the balloon is deflated and the distal end of the catheter is withdrawn.

CROSS REFERENCE TO RELATED APPLICATIONS

This Application claims the benefit of U.S. Provisional Application62/013,062, filed Jun. 17, 2014, which is incorporated herein byreference.

BACKGROUND

Obesity is widely recognized as a major public health issue resulting indecrease of quality of life and development of chronic diseases, such asmetabolic syndrome, diabetes, hypertension, congestive heart failure,atherosclerosis, sleep apnea, etc. Lifestyle changes can be used totreat obesity, but lifestyle changes are not always achievable,especially in long term prospect. Drug therapy is one conventionaltreatment for obesity, but it is often accompanied by variouscomplications and adverse side effects.

Bariatric surgery is another conventional treatment for obesity. One ofthe recognized benefits of bariatric surgery is the decreased productionof ghrelin. Ghrelin, a neuropeptide which is predominantly produced inthe gastric fundus, is the only known hormone that stimulates foodintake (orexigenic hormone). It is believed that the decreasedproduction of ghrelin that is associated with bariatric surgery helpspromote weight loss. But bariatric surgery is invasive and can beaccompanied by considerable surgical complications and/or adverse sideeffects.

SUMMARY OF THE INVENTION

One aspect of the invention is directed to a method of embolizing anartery in a living subject using a catheter. The catheter has a lumenthat provides a fluid tight path between a distal end of the catheterand a proximal portion of the catheter. The catheter also has a balloonlocated near the distal end of the catheter. This method includes thesteps of introducing the distal end of the catheter into the artery, andsubsequently inflating the balloon to form a seal that prevents blood inthe artery from flowing past the balloon. Subsequently, a first quantityof contrast agent is injected through the lumen into a portion of theartery that is distally beyond the balloon. Based on detected motion ofthe first quantity of contrast agent, a determination is made whetherthe balloon has formed an adequate seal. If it is determined that theballoon has not formed an adequate seal an adjustment is made to improvethe seal. After the adjustment is made, a mixture that includes embolicparticles and a second quantity of contrast agent is injected throughthe lumen into the portion of the artery that is distally beyond theballoon. A fluid that contains platelets is injected through the lumeninto the portion of the artery that is distally beyond the balloon, andthis step of injecting the fluid is implemented during or after the stepof injecting the mixture. Subsequently, the balloon is deflated.Subsequently the distal end of the catheter is withdrawn.

In some embodiments, the artery is a left gastric artery. In someembodiments, the step of injecting the fluid and the step of injectingthe mixture are implemented simultaneously. In some embodiments, thestep of injecting the fluid is implemented after the step of injectingthe mixture. In some embodiments, the fluid comprises platelet-richplasma. In some embodiments, the fluid comprises blood, and this bloodmay optionally be obtained from the subject using an introducer sheathbefore the blood is injected through the lumen, wherein the introducersheath is used to guide the catheter during the introducing step. Insome embodiments, the method further includes the step of injecting aquantity of blood through the lumen into the portion of the artery thatis distally beyond the balloon, and this step is implemented after thestep of injecting the first quantity of contrast agent and before thestep of injecting the mixture.

In some embodiments, the method further includes the steps of (a)injecting a third quantity of contrast agent through the lumen into theportion of the artery that is distally beyond the balloon, wherein thestep of injecting the third quantity of contrast agent is implementedafter the introducing step and before the inflating step; (b)determining, based on detected motion of the third quantity of contrastagent, whether the distal end of the catheter is in an appropriateposition; and (c) either (i) proceeding to the inflating step if it isdetermined, in step (b), that the distal end of the catheter is in anappropriate position, or (ii) adjusting the position of the distal endof the catheter if it is determined, in step (b), that the distal end ofthe catheter is not in an appropriate position.

Another aspect of the invention is directed to a method of embolizing anartery in a living subject using a catheter. The catheter has a lumenthat provides a fluid tight path between a distal end of the catheterand a proximal portion of the catheter. The catheter also has a balloonlocated near the distal end of the catheter. This method includes thesteps of introducing the distal end of the catheter into the artery, andsubsequently inflating the balloon to form a seal that prevents blood inthe artery from flowing past the balloon. Subsequently, a mixture thatincludes embolic particles and a first quantity of contrast agent isinjected through the lumen into the portion of the artery that isdistally beyond the balloon. A fluid that contains platelets is injectedthrough the lumen into the portion of the artery that is distally beyondthe balloon, and this step of injecting the fluid is implemented duringor after the step of injecting the mixture. Subsequently, the balloon isdeflated. Subsequently the distal end of the catheter is withdrawn.

In some embodiments, the artery is a left gastric artery. In someembodiments, the step of injecting the fluid and the step of injectingthe mixture are implemented simultaneously. In some embodiments, thestep of injecting the fluid is implemented after the step of injectingthe mixture. In some embodiments, the fluid comprises platelet-richplasma. In some embodiments, the fluid comprises blood, and this bloodmay optionally be obtained from the subject using an introducer sheathbefore the blood is injected through the lumen, wherein the introducersheath is used to guide the catheter during the introducing step.

In some embodiments, the method further includes the steps of (a)injecting a second quantity of contrast agent through the lumen into theportion of the artery that is distally beyond the balloon, wherein thestep of injecting the second quantity of contrast agent is implementedafter the introducing step and before the inflating step; (b)determining, based on detected motion of the second quantity of contrastagent, whether the distal end of the catheter is in an appropriateposition; and (c) either (i) proceeding to the inflating step if it isdetermined, in step (b), that the distal end of the catheter is in anappropriate position, or (ii) adjusting the position of the distal endof the catheter if it is determined, in step (b), that the distal end ofthe catheter is not in an appropriate position.

Another aspect of the invention is directed to an apparatus forembolizing an artery in a living subject. This apparatus includes acatheter having a lumen that provides a fluid tight path between adistal end of the catheter and a proximal portion of the catheter, and aballoon disposed near the distal end of the catheter. The balloon isconfigured to alternately (a) allow blood to flow through the arteryoutside the catheter when the balloon is in a deflated state or (b)prevent blood from flowing through the artery outside the catheter whenthe balloon is in an inflated state. The apparatus also includes a fluidtight chamber having an inflow port, an outflow port, and at least oneport for receiving contrast agent and embolic beads. The outflow port isfluidly coupled to the lumen at the proximal portion of the catheter.The apparatus also includes a first valve configured to selectively openor close the inflow port, a second valve configured to selectively openor close the outflow port, and at least one third valve configured toselectively open or close the at least one port for receiving contrastagent and embolic beads. The first valve, the second valve, and the atleast one third valve are configured to open an close in a sequence to(a) input embolic particles and a first quantity of contrast agent viathe at least one port for receiving contrast agent and embolic beads;(b) inject a mixture that includes the embolic particles and the firstquantity of contrast agent through the lumen via the outflow port, (c)input a fluid that contains platelets via the inflow port, and (d)inject the fluid that contains platelets through the lumen via theoutflow port.

In some embodiments, the at least one port for receiving contrast agentand embolic beads is implemented as a single port through which bothcontrast agent and embolic beads travel, and wherein the at least onethird valve is implemented using a single valve. In other embodiments,the at least one port for receiving contrast agent and embolic beads isimplemented as first port through which the contrast agent travels and asecond port through which the embolic beads travel, and wherein the atleast one third valve is implemented using separate valves for thecontrast agent and embolic beads, respectively. In some embodiments, theapparatus also includes an introducer sheath configured to extract bloodfrom the subject, and blood obtained using the introducer sheath is usedas the fluid that contains platelets. The introducer sheath isconfigured to guide the catheter during introduction of the catheter.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts an example of a suitable shape for the distal end of acustom-shaped guiding catheter with an S-shaped bend.

FIG. 2 is a graph that shows how the weight of the subjects changed overtime.

FIG. 3 is a graph that shows how the BMI (body mass index) of thesubjects changed over time.

FIG. 4 is a graph that shows how the ghrelin level in the subjects'blood changed over time.

FIG. 5 depicts an angiography of a left gastric artery before themicroparticles were delivered to their destination.

FIG. 6 depicts an angiography of the left gastric artery after thedistal portion of that artery was filled with microparticles.

FIG. 7 depicts a CT angiography of the left gastric artery and thesurrounding region three months after the distal portion of that leftgastric artery was filled with microparticles.

FIG. 8 depicts the distal end of a catheter that may be used to preventreflux of the microparticles.

FIG. 9 depicts the distal end of another embodiment of a catheter thatis designed to prevent reflux.

FIG. 10 depicts the distal end of another embodiment of a catheter thatis designed to prevent reflux.

FIG. 11 depicts an introducer sheath for use with the FIG. 10 catheter.

FIG. 12 depicts an exemplary embodiment of an extracorporeal device thatis used to orchestrate the flow of all the relevant substances inconnection with the FIG. 10 catheter.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Percutaneous endovascular modification of the function of the gastricfundus using particulate embolization of the distal portion of the leftgastric artery is less invasive and more cost effective alternative tobariatric surgery for achieving weight loss.

This application describes a novel approach which involves modifying thearterial blood flow to the gastric fundus by means of percutaneousendovascular flow reduction (or interruption) in the distal portion ofthe left gastric artery. Experiments in humans (performed outside theU.S.) has demonstrated dramatic weight loss at one month after procedureand sustained for six months follow-up with no reported adverse effects.While reduction in the hunger-mediating peptide hormone ghrelin(secreted in the gastric fundus) has been identified as a one ofpossible mechanism, the complete physiologic mechanism is not yet clearand may well involve other hormones and/or changes in gastric motilitywith consequent reduction in hunger sensation in experimental subjects.

The approach described herein achieves endovascular flow reduction orinterruption by introducing a plurality of particles into the distalportion of the subject's left gastric artery. The particles, alsoreferred to herein as microparticles, preferably have sizes between 300and 500 μm, and are delivered via a microcatheter. The particles arepreferably compressible and spherical. They are preferably made ofpolyvinyl alcohol, and more preferably made of acrylamido polyvinylalcohol. One suitable commercially available product for this purpose isBeadBlock Embolic Beads, 300-500 μm compressible microspheres(Biocompatibles UK Limited, Surrey, UK).

Alternative commercially available products for this purpose includepolyvinyl alcohol (PVA foam embolization particles, Cook Medical,Bloomington, Ind.); hydrogel core with Polyzene-F coating (Embozene™microspheres, CeloNova Biosciences, Inc., San Antonio, Tex.);microspheres made from trisacryl cross linked with gelatin (Embospheremicrospheres, Merit Medical Systems, Inc., South Jordan, Utah);HepaSphere™ Microspheres, which are made from two monomers (vinylacetate and methyl acrylate) that combine to form a copolymer (sodiumacrylate alcohol copolymer); Bearing™ nsPVA Embolization Particles,which are irregularly-shaped, biocompatible, hydrophilic, nonresorbableparticles produced from polyvinyl alcohol; EmboGold™ Microspheres, whichare made from trisacryl cross linked with gelatin and impregnated with2% elemental gold for visibility; QuadraSphere™ Microspheres, which arealso made from two monomers (vinyl acetate and methyl acrylate) thatcombine to form a copolymer (sodium acrylate alcohol copolymer), andTerumo Bead BlockT microspheres. In alternative embodiments, otherembolization materials may be used, including but not limited to coils,other microparticles, foams, different synthetic or organic gels,thrombin, fibrin, collagen, fibrinogen (liquid or powder), and any othermaterial that can occlude blood vessel.

Optionally, certain substances may be added to the particles (or to theother embolization materials) to enhance the effect of the procedure.Examples include, but are not limited to: pharmaceuticals, geneticmaterials, or different types of cells that also help to decreaseproduction of ghrelin and/or other hormones or other substances thateffect appetite in humans.

The procedure involves inserting a catheter into the left gastricartery, which is the major vessel that supplies gastric fundus andmodify blood flow. One way to accomplish this is to insert a guidingcatheter via the femoral artery or radial artery until the left gastricartery is engaged (in other words, until the distal end of the guidingcatheter is introduced into the subject's left gastric artery.) Althoughthe inventor is not aware of any guiding catheters that are speciallydesigned to engage the left gastric artery, examples of suitable guidingcatheters for this step include catheters that are already available forother applications such as for coronary angiography and or coronarystenting. In one preferred embodiment, the guiding catheter is a 6French Heartrail II JR-4.0 guiding catheter (Terumo Europe N.V., Leuven,Belgium). That particular guiding catheter is a Judkins Right typecatheter and has a JR-4.0 shape code. In alternative embodiments, acustom-shaped guiding catheter may be used for obtaining easy access toleft gastric artery. An example of one suitable shape for such a guidingcatheter is provided in FIG. 1, in which the distal end 12 of thecustom-shaped guiding catheter 10 has an S-shaped bend. This shape issimilar to the shape of the Surefire Axis Catheter (Surefire MedicalInc., Westminster Colo.), but the distal-most bend 14 is increased fromabout 45° to about 160°. Suitable dimensions for the guiding catheter 10for accessing the left gastric artery are as follows: A between 3 and 4inches; and B between ½ and 1 inch.

After the guiding catheter is in position, a microcatheter is thenguided through the guiding catheter and introduced into the mid segmentor distal portion of the subject's left gastric artery. Once the distalend of the microcatheter has been inserted into the mid segment ordistal portion of left gastric artery, the embolization material isdelivered into the distal portion of left gastric artery via themicrocatheter. The distal shaft of the microcatheter must be small,e.g., 2 French in diameter. One example of a commercially availablemicrocatheter that is suitable for this purpose is the Excelsior 1018Microcatheter (Boston Scientific Corp., Corck, Ireland).

The presence of the embolization material in the distal portion of leftgastric artery will reduce or interrupt the blood flow in the distalportion of left gastric artery, which will modify the blood supply tothe fundus of stomach. More specifically, it will reduce or interruptthe blood supply to the fundus.

Using microparticles for the embolization material (as opposed to othertypes of embolization materials) is advantageous because they are inert,biocompatible, and flow-directed. Moreover, when used as describedherein, they will not cause tissue necrosis or unwanted non-targetembolization. In contrast, if a chemical-based embolization materialsuch as sodium morrhuate is used instead of the preferredmicroparticles, deep penetration and or extravasation of thissclerotherapy agent into the gastric tissue may lead to local edemaand/or extensive inflammation that results in gastric ulceration andnecrosis. Chemical-based embolization material may also lead to systemictoxicity and non-target embolization that may damage the liver, spleenor other organs.

Using particles with sizes between 300 and 500 μm is advantageousbecause using smaller particles (e.g., 50-100 μm) can result in mucosalnecrosis of the fundus, and gastric ulcers. It can also result innon-target embolization of, for example, the esophagus, the liver,and/or the spleen because the small particles can penetrate very deepinto tissue and destroy gastric mucosa. Animal experiments have shownthat such smaller particles may also end up in structures other than thefundus. In addition, using larger particles (e.g., 700-1000 μm) canresult in gastric ulcers, and non-target embolization of, for example,the esophagus, the liver, and/or the spleen. This may be due todeformation of the particles during injections and the formation oflarger clusters, which can lead to more proximal embolization. It mayalso be due to reflux of the particles due to the Venturi effect. Incontrast, when particles with sizes between 300 and 500 μm are used,these problems are avoided or at least minimized.

Limiting the delivery of the particles to the distal portion of thesubject's left gastric artery is advantageous because when the proximalportion of the left gastric artery is also filled with particles, therisk of esophageal and nonfundus gastric ulcers is very high. Morespecifically, it was observed in three out of three subjects in animalstudies, when tested in pigs. In contrast, these problems were notobserved in any of the three pig subjects in which the delivery of theparticles was limited to the distal portion of the test subject's leftgastric artery.

Thus, by using the correct size of the correct material and deliveringit to the correct location, many of the problems associated with otherapproaches are avoided, and the procedure can be made safe.

EXAMPLE 1

A study was done on five obese subjects to determine the feasibility,safety, and efficacy of embolization of the distal portion of the leftgastric artery to reduce plasma ghrelin levels and body weight.

All subjects underwent gastroscopy prior the embolization to assess forthe presence of peptic ulcer or gastritis. Gastritis was found in twosubjects who subsequently underwent medical treatment. Embolization wasperformed only after follow-up gastroscopy showed significantimprovement in mucosal irritation.

Weights were measured and routine blood samples obtained including acomplete blood count, electrolytes, and creatinine prior toembolization.

In the procedure, 6-Fr femoral access was obtained. More specifically, a6-Fr Heartrail II JR-4.0 guiding catheter (Terumo Europe N.V., Leuven,Belgium) was used to engage the celiac trunk ostium and angiographyperformed in different projections in order to identify the origin andanatomy of left gastric artery. In some cases, a 0.35″ guidewire wasadvanced into the common hepatic or splenic arteries to stabilize theguiding catheter position.

The left gastric artery, a branch of the celiac trunk, was wired with a0.014″ Runthrough NS PTCA Guide Wire (Terumo Europe N.V., Leuven,Belgium) and an Excelsior 1018 Microcatheter (Boston Scientific Corp.,Corck, Ireland) advanced over the guide wire into the mid segment of theleft gastric artery. Subsequently, the guide wire was removed whilemaintaining the microcatheter position in the left gastric artery andselective angiography performed to ensure proper catheter position anddefine the anatomy and course of the left gastric artery. FIG. 5 is anangiography of the left gastric artery 50 and the surrounding anatomyafter a radio-opaque material was injected into the left gastric artery,but prior to the injection of any particles. The dark artifacts in thecircle 52 reveal that blood is flowing in the distal portion of the leftgastric artery.

Repeat injections of small amounts of BeadBlock Embolic Bead, 300-500 μmcompressible microspheres (Biocompatibles UK Limited, Surrey, UK) mixedwith contrast agent (1:1 ratio) were then performed. Angiography wasperformed between injections of the microspheres to assess left gastricartery flow characteristics. The injection of the microspheres wascontinued until distal portions of artery branches were no longervisible during radio-opaque contrast injection. This is shown in FIG. 6,which depicts the left gastric artery 50 and the surrounding anatomy.Note the absence of dark artifacts in the circle 52′, which indicatesthat blood is no longer flowing in the distal portion of the leftgastric artery.

The guiding and microcatheter were then withdrawn and subjectstransferred to a ward, where the introducer sheath was removed andmanual pressure applied to obtain hemostasis.

Esophagogastroscopy was performed in all subjects before and after theprocedure gastroscopy. A second follow-up gastroscopy was performed oneweek after the procedure. Weight and fasting plasma ghrelin levels wereobtained at baseline and the 1, 3, and 6-month follow-up visits. Toobtain the ghrelin levels, clotted blood samples were centrifuged toseparate out blood plasma. Fasting levels of ghrelin, ALT, AST, urea anduric acid were then measured. Ghrelin was measured using the HumanGhrelin (TOTAL) RIA KIT (Merck Millipore). Subject's weight and bodymass index (BMI) was also calculated at each of the visits.

Data for the study is presented below. Table 1 shows the subject data,Table 2 shows the weight at each visit for each subject, Table 3 showsthe corresponding BMI, and Table 4 shows the ghrelin levels at eachvisit for each subject. FIGS. 2, 3, and 4 depict the data in Tables 2,3, and 4, respectively, in a graphical format.

TABLE 1 Parameter Value Number of participants 5 Gender female/male (%)20/80% Age female/male (years) 44.7 ± 7.4 Weight (kg) 128.1 ± 24.4 BMI(kg/m2) 42.2 ± 6.8 Ghrelin (pg/ml)  473.4 ± 189.11

TABLE 2 Subject Initial weight Weight at Weight at Weight at # (kg) 1month FU 3 month FU 6 month FU 1 119 102 99 94 2 165 146 143 140 3 98 9085 80 4 131 120 116 117 5 127 117 114 107 Mean 128 ± 24 115 ± 21 111 ±22 108 ± 23 p Value 0.0032 0.0012 0.0008

TABLE 3 Subject Initial BMI at BMI at BMI at # BMI 1 month FU 3 month FU6 month FU 1 42 36 35 2 53 47 46 45 3 34 31 30 28 4 41 38 37 37 5 41 3838 34 Mean 42 ± 7 38 ± 6 37 ± 6 36 ± 6 p Value 0.0033 0.0012 0.001

TABLE 4 Initial Subject Ghrelin level Ghrelin level at Ghrelin level atGhrelin level at # (pg/ml) 1 month FU 3 month FU 6 month FU 1 459.6313.4 301.3 325.5 2 486.1 325.9 323.6 410.9 3 445.5 380.7 315.8 389.1 4501.2 341.6 299.7 388.6 5 478.3 342.2 325.5 391.3 Mean 470.54 340.76314.18 381.08 p Value 0.0015 0.0002 0.0042

STATISTICAL ANALYSIS: Statistical analysis was performed using computersoftware (SPSS 12.0 for Windows, Lead Technologies Inc. 2003. Chicago,Ill.). All values were presented as the mean±standard deviation (±SD).Comparison of weights and plasma ghrelin levels between different timepoints were done with the paired t-test. A p-value of <0.05 wasconsidered to determine statistical significance

RESULTS: There were no procedural complications. Three of the fivesubjects described mild transient epigastric pain after the procedure.However, follow-up gastroscopies on the day after embolization and at1-week follow-up did not reveal any abnormalities. All subjects reporteda significantly decreased appetite in the first days after theprocedure.

Significant progressive weight loss accompanied by reductions in plasmaghrelin levels was observed in all subjects at all follow-ups: Meanweight and BMI was reduced by 10%, 13%, and 16% at 1-, 3- and 6-monthfollow-up, respectively (Table 2 and3). Mean initial weight(128.12±24.4kg) decreased to 108±23kg (p<0.001). Blood plasma ghrelinlevels (initially 473±189) were significantly lower at 1- and 6-monthfollow-up (by 29% and 36% from baseline, p<0.05) and increased slightlyat the 6-month follow-up compared with 3-month follow-up while remaining18% lower from the baseline (p>0.05).

FIG. 7 is a CT angiograph the left gastric artery 70 and the surroundinganatomy that was taken 3 months after procedure. In this figure,portions where blood is flowing are indicated in white. Because thedistal portion of the left gastric artery is not visible in region 72,it is apparent that the distal portion remains occluded 3 months afterprocedure.

The data above demonstrates that embolization of the distal portion ofthe left gastric artery using microparticles is associated withsignificant reductions in plasma ghrelin levels and weight loss inhumans. It should be noted, however, that after an initial pronounceddecline in ghrelin levels after the procedure, the levels did increaseat the last follow-up visit (i.e., at the 6 month visit), Although thelevels were still lower than the pre-procedure baseline, a long-termstudy may be warranted to further investigate this increase.

The procedure described above appears to be safe. Specifically, therewere no incidences of ulcer formation or injury to remote structures.This may be related to the selective injection into the left gastricartery of beads that are large enough in size as to not allow systemicor remote toxicity, yet small enough to avoid the potential problemsdescribed above. Note that with more extensive embolization of arteriesother than the left gastric artery, the ulcer risk may be higher. Forexample, 40% of animals that underwent embolization of the left, short,and accessory gastric arteries developed gastric ulcers in a study byPaxton et al. These ulcers were located at the lesser curvature,suggesting a watershed effect. In addition, using the correct embolicmaterials as described herein apparently minimizes the extent andlikelihood of injury to adjacent or remote tissue.

It should be noted that this example was a non-randomized single-armfeasibility, safety, and efficacy trial with all its inherentlimitations. First, the absence of a control group does not allowdefinitive conclusions regarding efficacy. It is possible that theprocedure and study participation led to a higher motivation for dietcontrol and exercise. However, in this case, a decrease in plasmaghrelin levels should not be expected. Second, the intermediate-termfollow-up (i.e., 6 months) is too short to make conclusions regardinglong-term weight loss, as a rebound phenomenon with recurrent weightgain is conceivable. Third, though not observed in a study by theinventor, a risk of gastric ulcer formation may be significant but toosmall to have been observed in the study.

Microparticle-based embolization involves clinical risks includinggastric ulcer formation, esophageal and liver damage, which may resultfrom non target embolization and consequential retrograde and antegradereflux of micro particles due to high vascularity of the left gastricartery. In some embodiments, special provisions are made to prevent nontarget embolization and reflux of the particles, so that they do nottravel to other parts of the body. FIG. 8 depicts the distal end of acommercially available catheter (made by Surefire Medical Inc.) that canbe used for this purpose. In this embodiment, the wall 82 of thecatheter defines an internal lumen, and the particles are deliveredthrough that lumen, as indicated by the arrow labeled P. The distal end84 of the catheter flares out and preferably touches the inner walls ofthe artery 80 on all sides of the catheter. At least a portion of theflared distal end 84 is made of mesh, indicated by the “xxx” marking inFIG. 8. The mesh size is selected so that all types of blood componentscells can pass (including red blood cells, white blood cells, etc.), butthe microparticles cannot pass. A suitable spacing for the mesh for thispurpose is between 150 and 250 microns, and preferably about 200microns. As a result, even though the flared distal end 84 of thecatheter touches the walls of the artery 80, blood can still flow asindicated by the arrows B. The flow of blood helps to carry theparticles along to their destination in the distal portion of the leftgastric artery, and the mesh at the flared distal end 84 prevents theparticles from traveling backwards. However, because the left gastricartery has a relatively small diameter, the body of the catheter willblock a large portion of the artery, which will reduce the amount ofblood that can flow past the catheter. In this embodiment, the bloodflow could be reduced to the point where the blood flow will notadequate to direct the particles to their desired destination.

FIG. 9 depicts the distal end of a novel catheter that is designed toovercome this problem by maintaining significant blood flow while stillpreventing reflux of the particles. In this embodiment, the wall 92 ofthe catheter defines a first internal lumen, and the particles aredelivered through that lumen, as indicated by the arrow labeled P. Aballoon 98 located at the distal end of the catheter can be inflated ina conventional manner, and the balloon will prevent any particles fromrefluxing. The balloon 98 is preferably inflated with very low pressure(less than 1 atm), and is preferably designed to fail at low pressure(greater than 2 atm) in order to prevent barotrauma to the blood vessel.The balloon and catheter preferably have a hydrophilic-heparin coatingto further minimize vascular trauma.

When the balloon 98 is inflated, there will be no blood flow to helpcarry the particles along to their destination. To remedy this issue, asecond lumen 95 is provided in this embodiment. Blood will enter thesecond lumen 95 through input port 94 and exit the second lumen 95through output port 96, as indicated by the arrow labeled B---B.Preferably, at least one of the ports 94, 96 is covered with mesh. As inthe FIG. 8 embodiment, the mesh size is selected so that all types ofblood components cells can pass (including red blood cells, white bloodcells, etc.), but the microparticles cannot pass. A suitable spacing forthe mesh for this purpose is between 150 and 250 microns, and preferablyabout 200 microns. Due to the second lumen 95, blood can flow throughthe artery 90B even though the balloon 98 is inflated. The flow of bloodthrough the second lumen will be sufficient to carry the particles alongto their destination in the distal portion of the left gastric artery.In some preferred embodiments, the length of the lumen 95 is long enoughso that the input port 94 is disposed in a relatively wide portion ofthe vasculature, such as the celiac artery 90A (i.e., before the leftgastric artery 90B branches off from the splenic and common hepaticarteries, both illustrated schematically as 90C), or even the aorta (notshown). This arrangement will make it even easier for the blood to flowinto the input port 94, so that the blood flow can direct the particlesto their desired destination.

FIG. 10 depicts the distal end of another embodiment of a catheter 100that is designed to prevent reflux of the particles. In this embodiment,the sidewall 102 of the catheter surrounds a main internal lumen 103.Particles and blood are delivered through that main lumen 103 asindicated by the arrow 105. A balloon 98 located near the distal end ofthe catheter 100 can be inflated in a conventional manner, in which casethe balloon will prevent reflux of the particles that are injected viathe catheter 100. The balloon is 98 preferably inflated with very lowpressure (less than 1 atm), and is preferably designed to fail at lowpressure (greater than 2 atm) in order to prevent barotrauma to theblood vessel. The balloon 98 and catheter 100 preferably have ahydrophilic-heparin coating to further minimize vascular trauma. As inthe FIG. 9 embodiment, when the balloon 98 is inflated, there will be nobloodflow to help carry the particles along to their destination. Toremedy this issue, blood can be extracted from another portion of thepatient's body and injected into the proximal end of the main lumen 103.

FIG. 11 depicts an introducer sheath 110 that is suitable for extractingblood for this purpose. The introducer sheath has fluid-tight floor anda sidewall 111, preferably with at least one hole 112 disposed therein.When the introducer sheath is positioned at the catheter insertion site,blood from the patient's body can enter the holes 112 and exit theintroducer sheath 110 through exit port 117, as indicated by the inflowarrow B and the outflow arrow A. The outflow blood is provided to anextracorporeal device.

In some embodiments, this extracorporeal device is implemented using asimple manifold 120 as depicted in FIG. 12. The manifold 120 is a fluidtight chamber that is provided with inputs and outputs that make itsuitable for orchestrating the flow of all the relevant substances sothat the particles can be delivered to their intended destination in theleft gastric artery.

Appropriate tubing (not shown) is used to connect the exit port 117 ofthe introducer sheath 110 to the inflow port 123A of the manifold 120.Blood from the exit port 117 of the introducer sheath 110 that arrivesat the manifold 120 is depicted by arrow A. Appropriate outflow tubingis also used to connect the outflow port 123X of the manifold 120 to theproximal end of the catheter 100, in fluid communication with the mainlumen 103 of the catheter 100. Note that in alternative embodiments, theoutflow port 123X of the manifold 120 may be connected directly to theproximal end of catheter 100, instead of connecting those two partsusing tubing. The output of the manifold is depicted by arrow X, andthat output is routed back to the main lumen 103 of the catheter(depicted in FIG. 11 and FIG. 10) via the outflow tubing. Stopcocks 122Aand 122X are provided at the inflow port 123A and outflow port 123X ofthe manifold, respectively.

The manifold 120 has three stopcocks 127A, 127B, 127C, and three ports126A, 126B, and 126C that are configured to accept syringes connected atthe distal and of each of the stopcocks 127A-C. In FIG. 12, threesyringes 125A, 125B, and 125C are depicted as being connected to theseports 126A-C. The description below assumes that all five stopcocks127A-C, 122A, and 122X start out in the closed position. Note thatalthough the illustrated embodiment uses stopcocks, other types ofvalves may be used in place of stopcocks to control the flow of thevarious substances described herein (e.g., blood, contrast agent,particles, etc.).

To use the system, an introducer sheath 110 is installed at anappropriate entry position such as the femoral artery. The introducersheath 110 facilitates both insertion of the catheter and extraction ofblood from the patient's body. A guide wire (not shown) is advancedthrough the introducer sheath 110 in any conventional manner until thedistal end of the guide wire is disposed in the left gastric artery in aconventional manner. The catheter 100 is then introduced over the guidewire in a conventional manner until the distal end of the catheter 100is in the desired position in the left gastric artery 90B, as shown inFIG. 10. Optionally, the catheter 100 includes a radio opaque marker ator near the distal end to assist positioning. After the catheter hasbeen positioned in its desired location, the guide wire is removed.

An empty syringe 125A is then connected to port 126A, and stopcocks 122Aand 127A are opened. The plunger on the syringe 125A is withdrawn, whichdraws blood from the patient into the syringe 125A. The stopcocks 122Aand 127A are then closed. At this point, a quantity of blood (e.g.,between 1 and 20 cc, or between 5 and 10 cc) is temporarily being storedin the syringe 125A.

Syringe 125B is then filled with an appropriate quantity of contrastagent (e.g., between 1 and 20 cc, or between 5 and 10 cc) and connectedto port 126B. The stopcock 127B and 122X are opened and the plunger ofthe syringe 125B is depressed. Contrast agent will then flow into themanifold 120, out of the outflow port 123X and into the catheter 100.The contrast agent will exit the distal end of the catheter 100 (shownin FIG. 10). This step is used to assist in the correct placement of thedistal end of the catheter 100 in a conventional manner.

After it is determined that the distal end of the catheter 100 is in thedesired location (using any conventional approach), the balloon 98 isinflated in a conventional manner (e.g., using a fluid or gas that issupplied via an inflation lumen, not shown). Optionally, a secondinjection of contrast agent may be performed after the balloon inflationto verify that the balloon 98 has adequately sealed off the artery. Ifthe artery is not adequately sealed, appropriate adjustments may be madeand one or more additional injections of contrast agent may be made. Thestopcock 127B is now closed. Note that it may be necessary to refill thesyringe 125B with additional contrast agent if it is needed to implementthese steps.

Preferably, after the contrast agent has been injected, the catheter isflushed with all of the blood that was previously stored in the syringe125A. This can be accomplished by opening the stopcock 127A and fullydepressing the plunger of the syringe 125A. Alternatively, syringe 125Bmay be filled with sterile saline, and the sterile saline may be used toflush the catheter.

At this point in the procedure, the outflow stopcock 122X is closed andthe stopcock 127A is opened. If syringe 125B does not contain enoughcontrast agent to implement the following steps, the syringe 125B shouldbe refilled with additional contrast agent. A syringe 125C containingthe embolic particles mixed with a liquid in a conventional manner isnow connected to the port 126C and the stopcocks 127B and 127C are open.The plungers on the syringes 125B and 125C are then depressed. Thisinjects the particles from the syringe 125C and the contrast agent fromthe syringe 125B. The contents of both these syringes will then flowthrough the manifold 120 and back up into the syringe 125A because boththe inflow stopcock 122A and the outflow stopcock 122X are closed atthis point. Stopcocks 127B and 127C are then closed and the outflowstopcock 122X is opened. The plunger on the syringe 125A is thendepressed, which injects the mixture of particles and contrast agentfrom the syringe 125A into the manifold 120. Preferably the plunger isdepressed at a slow speed. From the manifold 120 the mixture will flowout of the outflow port 123X and through the catheter 100, and will exitthe catheter 100 and flow into the distal portion of the left gastricartery 90B (shown in FIG. 10). The outflow stopcock 122X is then closed.

Note that in alternative embodiments, instead of supplying the particlesand the contrast agents from separate syringes 125B and 125C, those twocomponents can be premixed into a single syringe 125C, and injecteddirectly from that single syringe 125C into the manifold 120, afterwhich the path of the mixture will continue as indicated above.

After the particles have been delivered to their intended destination inthe left gastric artery, it is preferable to deliver a quantity of blood(e.g., 1-5 cc) to the left gastric artery to help carry the particles totheir destination in the artery, and so that the blood can interact withthe particles, which will help block the flow of blood to more distalportions of the left gastric artery. To accomplish this, stopcock 127Aand the inflow stopcock 122A is opened and the plunger of the syringe125A is withdrawn to extract blood from the patient. The inflow stopcock122A is then closed and the outflow stopcock 122X is opened. The plungeron the syringe 125A is then depressed, which pumps the blood from thesyringe 125A through the manifold 120 and the catheter 100 and deliversthe blood to the left gastric artery. Preferably the plunger isdepressed at a slow speed. In alternative embodiments, instead ofinjecting the blood after the mixture of particles and contrast agenthas been injected, a quantity of blood can be mixed in with theparticles and the contrast agent, and all three of those components canbe injected simultaneously.

Use of the patient's own blood as described above preferred. The flow ofthe patient's own blood will mimic the patient's own native circulationto help carry the particles to their intended destination. Inalternative embodiments, a different fluid that contains platelets(e.g., platelet-rich plasma) may be used instead of whole blood tointeract with the particles. The platelets in the fluid will interactwith the particles to (e.g., by forming a thrombosis) to help block theflow of blood to more distal portions of the left gastric artery.

All the stopcocks are then closed, the balloon 98 (depicted in FIG. 10)is deflated, the system is detached, and the catheter 100 is withdrawn.In some embodiments, a small barrel syringe (1-3 cc) is used toimplement the syringe 125A, to facilitate the injections of blood andthe bead/contrast mixture. This variety of syringe is advantageous sincethe force required to push the plunger will be reduced. However, due tothe small volume of this variety of syringe, the steps to fill syringe125A may require repetition in order to inject the desired volumes ofthe relevant substances.

Blood pressure is preferably monitored before, during, and after theprocedures described above. Note that while FIG. 12 depicts a manualdevice for implementing the procedure described above, in alternativeembodiments, the manifold 120 can be replaced with other extracorporealdevices, including but not limited to an automated system (not shown)with suitable valves and pumps configured to implement similarfunctionality as the manifold 120 and syringes 125A-C described above.

The technique of active delivery of blood described above in connectionwith FIGS. 10-12 may be more advantageous than relying on passive bloodflow (as described above in connection with FIG. 9). This is becausepassive flow may be restricted or otherwise affected, by physiologicalcircumstances, such as vasoconstriction and changes in blood pressure,which may go unnoticed. On the other hand, by using the embodiment ofFIGS. 10-12, the physician can control the active delivery of blood, andadequate blood flow can help improve embolization and increase the ofnumber of particles delivered to target area. Also, with activedelivery, the blood may be delivered in precise sequences, which mayimprove targeting of the embolization.

Note also that the methods and apparatus described above in connectionwith FIGS. 10-12 may also be used with different embolization materials,including but not limited to onyx, fibrin glue, and radioactive beads.

The FIG. 10-12 embodiment described above is designed for controlled,safe, targeted delivery of embolic agents using VLP balloon occlusionwith controlled expansion to minimize barotrauma and autoperfusioncapability for sequential blood infusion to enhance targetedembolization and ability to measure pressure to control delivery ofparticles.

Two studies were done to test the FIG. 10-12 embodiment. Pigs werechosen for these studies because of the anatomical similarities with ahuman's organs (e.g., gastric fundus, and gastric and peripheralarteries). Moreover, a pig's vasculature is accessible with conventionalequipment, such as a diagnostic and guiding catheters, which allowed forthe evaluation of pigs arteries by angiography and results ofembolization. Gross anatomical analysis was performed in both studies toevaluate overall tissue architecture, ulcerations, damage or infarctionto different organs.

One study was implemented in the kidneys, liver, and spleen of two pigs,using both the FIG. 10-12 embodiment and a conventional Maestro-MeritMedical microcatheter (with no manifold) as a control in differentarteries of the relevant organ in each pig. In this study, angiographydemonstrated better microparticle penetration with the FIG. 10-12embodiment, demonstrated by contrast density, complete filling of targetsegment of kidneys, different segments of liver and spleen and enhancedtissue interaction. The usage of contrast agent and embolic beads wassignificantly lower for the FIG. 10-12 embodiment versus the control.Additionally, angiography before and during embolization demonstrated noreflux with the FIG. 10-12 embodiment, versus significant retrogradereflux in the control sites.

A second study was implemented as an initial evaluation of safety andefficacy of the FIG. 10-12 embodiment to reduce plasma ghrelin levelsand body weight in pigs. In this study, embolization of the left gastricartery of 9 pigs was performed using micro particles (Embo shield, MeritMedical, Salt Lake City, Utah) of 300-500 micrometer size. In six pigs,(two acute and four with a one month follow-up), the embolization wasperformed using the FIG. 10-12 embodiment. In the remaining three pigs(one acute and two with a one month follow-up), the embolization wasperformed using a conventional Maestro-Merit Medical microcatheter (withno manifold) as a control. Safety and efficacy was evaluated byangiography, gross anatomy and histology (H&E and Imunno staining) andweight gain in the chronic animals.

The weight and ghrelin level data for the second study were as follows:

TABLE 5 Subject Initial weight 1 week 2 weeks 3 weeks 4 weeks # (kg)(kg) (kg) (kg) (kg) Control A 32.2 34.0 36.5 35.2 33.8 Control B 37.138.0 42.0 43.7 42.6 1 29.0 30.9 35.6 34.1 33.8 2 32.3 29.0 28.1 26.830.0 3 30.5 33.6 34.3 30.9 29.1 4 36.1 36.8 36.7 30.5 28.9

TABLE 6 Subject Initial ghrelin 1 week 2 weeks 3 weeks 4 weeks # (pp/ml)(pp/ml) (pp/ml) (pp/ml) (pp/ml) Control A 640 550 576 563 538 Control B589 501 477 495 442 1 701 580 568 554 533 2 789 647 592 568 537 3 631473 504 454 ??? 4 680 530 496 414 442

Atraumatic navigation of small tortuous vessels for LGA embolization wasachieved with the FIG. 10-12 embodiment. There was better beadpenetration with FIG. 10-12 embodiment versus the control demonstratedby contrast density, with complete filling of target segment. The FIG.10-12 embodiment also required less contrast agent and embolic beadsthan the control. Angiography of the left gastric artery demonstrated noreflux in all six pigs for the FIG. 10-12 embodiment, versus significantretrograde and antegrade reflux in all 3 control animals. Gross anatomyrevealed targeted embolization of the gastric fundus with the FIG. 10-12embodiment, versus damage of esophagus, liver and gastric pylorus andbody in all three control animals.

The second study also quantitatively measures the Ghrelin positivepopulation in the fundus, body and pyloric regions of the stomach byimmunohistochemistry and histomorphometry. Twelve tissue sections fromthe fundus, two tissue sections from the body and two tissue sectionsfrom the pyloric regions were taken for routine paraffin embedding andsectioning. Four-micron histologic sections were stained with routineH&E stain and immunohistochemical stain for Ghrelin (Ghrelin [Porcine]antibody for IHC, catalog #H-031-52, Phoenix Pharmaceuticals, Inc, 330Beach Road, Burlingame, Calif. 94010, USA (800) 988-1205) at 1:2000dilution. These slides are scanned with a whole-slide scanner using the20×objective (Aperio ScanScope System, Aperio Technologies, Inc. 1360Park Center Drive, Vista, Calif. 92081 866-478-4111). Using the AperioScanScope software with the Genie and the nuclear algorithms we measuredthe mucosal area and the number of brown staining Ghrelin positivecells. The algorithm was validated against the manual count with anaverage discrepancy of 3.05% excluding the three histologic sectionoutliers.

This testing revealed that the FIG. 10-12 embodiment resulted insignificantly fewer Ghrelin Positive Cells Cells/MM2 in the fundusversus the control, as indicated in the table below.

TABLE 7 Ghrelin cells in fundus of stomach after embolization Number ofArea of Mucosa Ghrelin Positive Ghrelin Positive (mm²) Cells Cells permm² FIGS. 10-12 10.11 ± 14.17 310.88 ± 360.23 23.63 ± 14.86 embodiment(n = 4) Control (n = 2) 21.75 ± 8.23  512.77 ± 345.94 57.26 ± 19.11

CONCLUSIONS: Percutaneous embolization of the distal portion of the leftgastric artery with embolic beads as described in the study is feasibleand appears to be safe. It leads to a reduction in plasma ghrelin levelsand is accompanied by a significant weight loss at intermediate termfollow-up. It may be a good tool to enhance weight loss in subjects withmorbid obesity who cannot achieve weight loss by conventional means(diet and exercise) and an alternative to or complimentary to bariatricsurgery.

Note that while the embodiments described above are described in thecontext of the left gastric artery and the fundus of the stomach,similar techniques may be used in other arteries to embolize differentportions of a patient's anatomy. Examples include, but are not limitedto, portions of the stomach that are adjacent to the right gastricartery, the short gastric artery, the gastro-epiploic artery, the rightgastro-omental artery, the left gastro-omental artery, or any branchesthereof. In these alternative anatomic regions, the same apparatus andmethods described above may be used. Alternatively, appropriatemodifications may be made to optimize the apparatus and methods to otherportions of the anatomy.

While the present invention has been disclosed with reference to certainembodiments, numerous modifications, alterations, and changes to thedescribed embodiments are possible without departing from the sphere andscope of the present invention, as defined in the appended claims.Accordingly, it is intended that the present invention not be limited tothe described embodiments, but that it has the full scope defined by thelanguage of the following claims, and equivalents thereof.

What is claimed is:
 1. An apparatus for embolizing an artery in a livingsubject, the apparatus comprising: a catheter having a lumen thatprovides a fluid tight path between a distal end of the catheter and aproximal portion of the catheter; a balloon disposed near the distal endof the catheter, wherein the balloon is configured to alternately (a)allow blood to flow through the artery outside the catheter when theballoon is in a deflated state or (b) prevent blood from flowing throughthe artery outside the catheter when the balloon is in an inflatedstate; a fluid tight chamber having an inflow port, an outflow port, andat least one port for receiving contrast agent and embolic beads,wherein the outflow port is fluidly coupled to the lumen at the proximalportion of the catheter; a first valve configured to selectively open orclose the inflow port; a second valve configured to selectively open orclose the outflow port; at least one third valve configured toselectively open or close the at least one port for receiving contrastagent and embolic beads; and an introducer sheath configured to extractblood from the subject, wherein the first valve, the second valve, andthe at least one third valve are configured to open an close in asequence to (a) input embolic particles and a first quantity of contrastagent via the at least one port for receiving contrast agent and embolicbeads; (b) inject a mixture that includes the embolic particles and thefirst quantity of contrast agent through the lumen via the outflow port,(c) input a fluid via the inflow port, and (d) inject the fluid throughthe lumen via the outflow port, wherein blood obtained using theintroducer sheath is used as the fluid, and wherein the introducersheath is configured to guide the catheter during introduction of thecatheter.
 2. The apparatus of claim 1, wherein the at least one port forreceiving contrast agent and embolic beads is implemented as a singleport through which both contrast agent and embolic beads travel, andwherein the at least one third valve is implemented using a singlevalve.
 3. The apparatus of claim 1, wherein the at least one port forreceiving contrast agent and embolic beads is implemented as first portthrough which the contrast agent travels and a second port through whichthe embolic beads travel, and wherein the at least one third valve isimplemented using separate valves for the contrast agent and embolicbeads, respectively.